Persistent pain and cutaneous hyperalgesia are associated with many painful syndromes. Traditional pain management approaches, such as with narcotics, are problematic due to their adverse side effects such as tolerance and addition. Analgesic properties of cannabinoid drugs have been acknowledged for many years but it is only recently that the underlying neural mechanisms are being elucidated. Although cannabinoids have been traditionally believed to produce their antinociceptive properties through actions in the central nervous system, recent evidence suggests that cannabinoids may produce antinociception peripherally. Moreover, low doses of cannabinoids may be very effective in relieving hyperalgesia. The proposed studies will investigate the peripheral neural mechanisms that contribute to cannabinoid-mediated antinociception. Our preliminary data suggest that 1) cannabinoid receptors are located on dorsal root ganglion (DRG) neurons that contain calcitonin gene-related peptide (CGRP); 2) intraplantar and intrathecal injection of cannabinoids prevent the development of hyperalgesia produced by capsaicin; 3) cannabinoids decrease evoked release of GCRP from cultured DRG neurons. To further investigate peripheral mechanisms of cannabinoid antinociception, we propose: to determine antihyperalgesic properties of intarplantar and intrathecal cannabinoids using the capsaicin and carrageenan models of inflammation (Aim 1); to determine whether cannabinoids reduce sensitization of cutaneous nociceptors produced by capsaicin and carrageenan (Aim 2); and to determine whether cannabinoids decrease transmitter release from primary afferent fibers in vitro and in vivo, and investigate underlying mechanisms. These studies will provide new information on the mechanisms by which cannabinoids produce antinociception. Moreover, results will have direct clinical significance if cannabinoids attenuate hyperalgesia through peripheral mechanisms. Peripheral cannabinoids may be very effective for managing certain chronic pains without undesirable side effects associated with traditional therapies.